Mass spectrometry is used for analyzing substances that can be brought to the gas phase under high-vacuum conditions, i.e. under pressures generally ranging between about 10−2 and 10−6 Pa or lower. Although the present subject matter is not limited to this field of use, reference in the following description will therefore be made primarily to this analysis method.
Mass spectrometry is a known analytical technique applied to both the identification and analysis of known substances. The principle on which it is based is the possibility of separating a mixture of ions depending on their mass/charge (m/z) ratio generally by applying electric or magnetic fields, either static or oscillating.
There are different ways to volatize and ionize a sample, and there are many different kinds of ion sources, such as EI (electron impact) source, FAB (fast atom bombardment) source, ESI (electro-spray ionization) source, MALDI (matrix assisted laser desorption and ionization) source. One of the most frequently used sources is the electronic impact EI source, wherein the substance of the sample either spontaneously evaporates or is already in the gas phase. A known energy electron flow hits the molecules of the sample, which are changed into positive ions by losing one or more electrons. The ions are then accelerated by an electrostatic field and directed towards the analyzer.
The diagram reporting the concentration of each ion versus the mass/charge (m/z) ratio, known as the mass spectrum, is distinctive of each compound as it is directly correlated to the chemical structure thereof as well as to the ionization conditions to which the compound is subjected. Typically, the mass spectrum is a series of peaks indicative of the relative abundances of detected ions as a function of their m/z ratios. The instruments employed in the mass spectrometry field, known as mass spectrometers, generally comprise three main units arranged in series: an ion source to volatize and ionize the sample, an analyzer to select the ions produced by the source according to the mass/charge ratio; and a detector to detect the ions coming from the analyzer. The mass spectrometer may also include electronics for processing output signals from the detector as needed to produce a user-interpretable mass spectrum.
The ion source is the part of the mass spectrometer entrusted to change the molecules of the sample into ions through the ionization phenomenon. Moreover the produced ions must be free to move in space for measurement of the m/z ratio. In certain “hyphenated” or “hybrid” systems, the sample supplied to the ion source may first be subjected to a form of analytical separation. For example, in a gas chromatography-mass spectrometry (GC-MS) system, the output of the GC column may be transferred into the ion source through appropriate GC-MS interface hardware.
The analyzer is the part of the mass spectrometer allowing for selecting the mass/charge (m/z) ratio of the ions produced by the source. Also this measurement can be carried out in many ways, so long as the ions can freely move in the spectrometer without colliding with air molecules, which is achieved by providing high-vacuum conditions therein.
According to the prior art, analyzers are mainly classified as magnetic analyzers, Omegatron analyzers (the mass selection is carried out by using a magnetic field and a RF field), quadrupole analyzers, ion-trap analyzers, FT-ICR (Fourier Transform Ion Cyclotron Resonance) analyzers, TOF (time of flight) analyzers, cycloidal mass analyzers (the mass selection is carried out through a suitable selection of the resulting electric and magnetic field), magnetic-sector and ion-trap analyzers, optic spectroscopy cross-wire analyzers (measurement of the spectra of either emission or absorption light, or of photons' effects on the analyzed sample). In the present work reference is made, by way of example, to the magnetic quadrupole, and ion-trap analyzers.
The magnetic analyzer comprises a bent tube immersed into a magnetic field perpendicular thereto. The magnetic field makes the ions cover a bent trajectory. The bend radius depends on the entering ions energy and on the magnetic field B. The ion exits the analyzer only if the ion trajectory corresponds to the tube bend. If the ion bends more or less than the tube bends, it collides with the tube walls and is neutralized. Therefore, for each value of the magnetic field only ions having a certain m/z ratio and a certain kinetic energy pass through the analyzer, while the others are removed. From the value of the magnetic field and from the kinetic energy it is possible to go back to the m/z ratio of the ion selected by the analyzer. In this way the mass spectrum, which is the graph of the intensity of the ionic current detected by the detector, is obtained depending on the m/z ratio selected by the analyzer. In a mass spectrum, the presence of a peak at a certain value of m/z indicates that the source is producing ions having that m/z ratio.
Another kind of analyzer frequently employed in the mass spectrometry is the quadrupole analyzer. Generally, a quadrupole is a device composed of four metal parallel bars. Each pair of diagonally opposed bars is electrically linked together and a RF (radio-frequency) voltage is applied between one pair of bars and the other pair. A direct current voltage is then added to RF voltage. Ions oscillate during the flight among the quadrupole bars. Only the ions having a certain m/z ratio pass through the quadrupole and reach the detector for a given ratio of the two voltages: the other ions undergo unstable oscillation and collide with the bars. This allows either the selection of a particular ion, or the scanning of the range of the masses by means of the voltage variation.
A further example of a mass analyzer consists of an ion-trap. Based on a physical principle similar to the one of the quadrupole, the ion-trap keeps all the ions within the trap and makes them selectively free upon varying of the intensity of an oscillating electric field.
The detectors generally comprise dynodes, i.e. electronic multipliers able to amplify the very feeble current produced by the ions passed through the analyzer. The signals obtained in this way are subsequently transmitted to a computer able to represent, with the aid of suitable software, the amount of each ion depending on its mass, i.e. the final mass spectrum. Moreover, the use of computers allows the instrument parameters to be quickly combined with the literature search in libraries of electronically formatted spectra, so as to automate the identification of compounds according to their spectra and to the operative conditions with which the analysis has been carried out.
With reference to FIG. 1, a mass spectrometer device of the kind based on an electronic impact source and on a quadrupole mass analyzer according to the known art is schematically shown. In FIG. 1, the device is denoted as a whole with the reference numeral 11 and it comprises an entrance section 11a, an ionization section 11b, an analysis section 11c and a detection section 11d. 
The entrance section 11a is generally intended for being immersed in the ambient to be sampled, which generally reaches the atmospheric pressure, from which the gas to be sampled, or analyte, enters the device. To this purpose the entrance section 11a substantially comprises a capillary tube 13 with which a heater 15 is associated. The heater, for instance, has an electric resistance wound around the capillary tube 13. As it is known, to avoid effects due to absorption/desorption along the walls of the introduction system of gas, it is advisable to make a suitable choice of the materials as well as operating at a reasonably high temperature, for instance 100° C., which further allows for avoiding gas condensation phenomena.
In accordance with a prior art embodiment, the capillary tube 13 leads to a first transition chamber 17 defined inside a corresponding flange 19, and is discharged by means of a high-vacuum pump 21. The pump 21 for instance can be a turbo-molecular pump, associated through a duct 23 at a radial side door 25 and presenting the entrance axial primary door 43 associated with the casing 41 of the device.
Downstream of the first transition chamber 17 a second micro-capillary tube 27, for instance having an about 20 μm diameter and being about 1-2 mm long, is provided. The micro-capillary tube 27 communicates, in turn, with a second transition chamber 29, associated with the ionization section 11b, wherein the gas to be sampled is collected downstream the micro-capillary tube 27.
In the shown example, the ionization section 11b comprises an electronic impact (EI) source, wherein an ionization chamber 31 equipped with ionization device 33, for instance ionization filaments, is defined. Moreover, permanent magnets can be provided for increasing the source efficiency: in this way the electrons actually describe spiral trajectories so increasing the total path inside the source. Electrostatic lenses 35 are provided downstream the ionization chamber 31 in the transition area between the ionization chamber 33 and the following analysis section 11c. In the ionization chamber the molecules of the sample to be analyzed, which are in the gas phase, interact with an electron beam generated by an incandescent filament and accelerated through an adjustable potential. The beam energy is normally ranges between about 10 and 100 eV.
The analysis section 11c comprises a quadrupole device 37 downstream with the detection section 11d comprising a detector 39, for instance a Faraday cup detector and/or a SEM (secondary electron multiplier) detector or a Channeltron detector, is provided. The analysis section 11c and the detection section 11d are housed in the casing 41 at a pressure of generally on the order of at least 10−3 Pa, obtained through the turbo-molecular pump 21 associated through the corresponding axial primary door 43.
Calibrated leak devices are also known in the art. Devices of this kind allow generation of controlled gas flows through the membrane as well as to quantificate leakages value, by calibrating the instruments required to detect them, during tight tests. The currently used devices are substantially of two kinds: orifice leaks, or capillary, and helium permeation leaks. The first ones, also called pinholes, are generally made by laser ablation or chemical etching. Such technologies enable apertures to be manufactured with high precision and reproducibility. An example of the first kind of devices having membranes with nanoholes (holes passing through the membrane and having a nanometric size diameter) is disclosed in U.S. Pub. No. 2006/0144120. Devices of this kind allow for generating controlled gas flows through the membrane as well as to quantificate leakages values by calibrating the instruments required to detect them during tight tests. Another example of this kind of membrane is disclosed in WO 03/049840.
The permeation leaks however have a very unstable behavior when the temperature changes (their value varies of about 3% per centigrade grade in case of temperature values around room temperature), and long response times. They are fragile (being made of glass, they are easily breakable even when they only fall to the ground), only suitable for helium and have a single flow value. Examples of such permeation leaks are described in DE 19521275 and WO 02/03057.
Gas sampling devices based on permeation leaks are also disclosed in U.S. Pat. No. 4,008,388, U.S. Publication No. 2002/134933, U.S. Pat. No. 4,311,669, U.S. Pat. No. 4,712,008 and WO2008/074984. Selectively permeable membranes used in the field of mass spectrometry are also disclosed in U.S. Pat. No. 4,551,624 and Maden A M et al.: “Sheet materials for use as membranes in membrane introduction mass spectrometry,” Anal. Chem., Am. Chem. Soc., US vol. 68, no. 10, 15 May 1996, pages 1805-1811, XP000588711 ISSN: 0003-2700.
Nanohole membranes of the above first species should not be confused with gas permeable membranes. Membranes of the first kind have holes made artificially, e.g. by focused ion beam (FIB) or laser drilling, having substantially regular cross section along the whole length of the hole, and for this reason can be calibrated according to the use of the membrane. In addition, several or many practically identical holes with parallel axes can be produced on the same membrane. On the contrary, gas permeable membranes are membranes whose natural property of the material allows for permeability of a gas or a gas mixture usually at a high temperature. In addition, gas permeable membranes may be selective in the type of gas allowed to permeate through the membrane, while nanohole membranes are not selective.
As it will be easily appreciated from the preceding description of a gas analyzer according to the known art, the entrance section and the ionization section are considerably complex both for the number of the components and for the fact that such components must be high-vacuum tight associated with each other, resulting in high costs. Moreover, the prior art devices must be equipped with vacuum pumps having considerable flow capacities as they have to absorb the flow entering the ionization chamber, which is generally high.
In addition to the foregoing considerations, to improve mass accuracy and resolution MS systems require calibration to correct for errors caused by various sources, such as drifts in instrument performance and response that may occur during an MS analysis and/or from one analysis to the next analysis. Calibration may entail introducing one or more calibrants into the mass spectrometer during an analysis or between analyses. A calibrant may be a known reference compound having a known response (e.g., peaks at specified m/z ratios) when processed by a given MS system. A calibration process may entail, for example, operating the MS system to make actual measurements of the calibrant ions, comparing the measurements to known measurements, and making adjustments to one or more components of the MS system as needed to tune the MS system. Conventionally, a relatively large amount of calibrant is injected into a mass spectrometer, which may have an adverse effect on the measurement of analyte ions derived from a sample of interest. Complex and costly vacuum pumping systems are often needed to successfully evacuate the calibrant from the mass spectrometer so as to minimize adverse impact on sample analysis. Moreover, again to minimize adverse impact on sample analysis, the use of a large amount of calibrant often results in a large period of “recovery” time being required to enable the mass spectrometer to be brought to standard operating conditions suitable for sample analysis. Additionally, the calibrant may clog up the small-bore capillaries often utilized to introduce gases into the ion sources of MS systems, such as electron ionization (EI) sources and chemical ionization (CI) sources.
Therefore, there continues to be a need for improved systems, devices and methods for calibrating MS systems.